Disrupted Adenovirus Serotype 5-based Anti-cocaine Vaccine

描述(申请人提供)：可卡因成瘾是一个主要问题，目前还没有有效的治疗方法。由于成瘾是一种慢性复发性疾病，其特征是反复使用药物和戒毒，因此接种可卡因疫苗可能是终生的治疗方法。开发抗可卡因疫苗的挑战在于可卡因是一种小分子，免疫系统看不见。以前将可卡因作为半抗原连接到蛋白质载体上取得的成功有限，可能是因为蛋白质载体没有足够的免疫原性来激发高亲和力、高滴度的抗体，足以阻止可卡因到达大脑中的受体。我们开发了一种新的策略来激发对可卡因的免疫力，利用腺病毒(Ad)衣壳蛋白在人类中具有高度免疫原性的知识。我们假设，将可卡因类似物与Ad衣壳蛋白联系起来，将产生针对可卡因的高亲和力、高滴度抗体，足以隔离系统给药进入大脑，从而抑制可卡因诱导的行为。我们的战略是，我们可以通过破坏Ad来避免任何感染病毒的风险，因为我们的概念是，由可卡因类似物与被破坏的衣壳蛋白组成的疫苗将保留完整Ad的免疫佐剂特性。基于这些概念，我们开发了dAd5GNE，一种被破坏的E1-E3-5型Ad，带有Gne，一种稳定的可卡因类似物，与Ad衣壳蛋白共价连接。在小鼠、大鼠和非人灵长类动物中，dAd5GNE可诱发持久、高滴度、高亲和力的抗可卡因抗体。在反复静脉注射可卡因后，dAd5GNE疫苗可有效地消除可卡因诱导的小鼠多动，限制大鼠的多动和可卡因自身给药行为，并阻断可卡因在非人灵长类动物中对其同源中枢神经系统受体的访问。这项提案的重点是将dAd5GNE转化为临床研究，制造GMP级疫苗，在实验动物中证明安全性，获得监管部门的批准，并开展I期临床研究以评估安全性和初步疗效措施。为实现这一目标，我们制定了以下具体目标。目的1.建立规模化的dAd5GNE生产工艺，优化dAd5GNE的生产、纯化和性质，并将这些方法转移到我们的GMP实验室，验证生产工艺，生产GMP临床级dAd5GNE疫苗。目的2.对dAd5GNE产品进行启用IND的临床前疗效和安全性测试。目的3.准备和提交IND包，并获得FDA和其他监管团体的批准，以启动I期临床试验。目的4.开展第一阶段试验，评估dAd5GNE疫苗在人体内的安全性和有效性的初步措施。 公共卫生相关性：可卡因成瘾是一个主要的健康问题，目前还没有有效的治疗方法。我们开发了一种抗可卡因疫苗dAd5GNE，它是一种高度免疫原性的扰乱5型人腺病毒的病毒，与可卡因类似物偶联。基于对小鼠、大鼠和非人灵长类动物的研究表明，dAd5GNE在激发抗可卡因抗体和抑制可卡因到达大脑的能力方面是高效的，我们建议开展临床前研究，获得监管部门的批准，并在可卡因成瘾者中进行dAd5GNE的I期安全性和初步疗效试验。

DESCRIPTION (provided by applicant): Cocaine addiction is a major problem for which there is no effective therapy. Because addiction is a chronic relapsing illness, characterized by cycles of drug use and abstinence, vaccination against cocaine could be a lifetime therapeutic. The challenge in developing an anti-cocaine vaccine is that cocaine is a small molecule, invisible to the immune system. Previous linking of cocaine as a hapten to a protein carrier has had limited success, likely because the protein carrier has not been sufficiently immunogenic to evoke high affinity, high titer antibodies sufficient to block cocaine from reaching its receptors in the brai. We developed a novel strategy to evoke immunity to cocaine, leveraging the knowledge that adenovirus (Ad) capsid proteins are highly immunogenic in humans. We hypothesized that linking a cocaine analog to Ad capsid proteins would elicit high-affinity, high-titer antibodies against the cocaine, sufficient to sequester systemically administered drug from access to the brain, thus suppressing cocaine-induced behavior. We strategized that we could avoid any risk of the infectious virus by disrupting the Ad, with the concept that a vaccine comprised of the cocaine analog coupled to disrupted capsid proteins would retain the immunologic adjuvant properties of intact Ad. Based on these concepts, we developed dAd5GNE, a disrupted E1- E3- serotype 5 Ad with GNE, a stable cocaine analog, covalently linked to the Ad capsid proteins. In mice, rats and nonhuman pri- mates, dAd5GNE evoked persistent, high titer, high affinity IgG anti-cocaine antibodies. dAd5GNE vaccination was highly effective in abrogating cocaine-induced hyperactivity in mice, following repetitive intravenous doses of cocaine, limiting both hyperactivity and cocaine self-administration behavior in rats, and blocked cocaine access to its cognate CNS receptors in nonhuman primates. The focus of this proposal is to translate dAd5GNE to a clinical study, manufacture GMP grade vaccine, demonstrate safety in experimental animals, obtain regulatory approval and carry out phase I clinical studies to evaluate safety and preliminary measures of efficacy. To accomplish this, we have formulated the following specific aims. Aim 1. Develop a scaled-up process and optimize production, purification and characterization of dAd5GNE, transfer the methods to our GMP facility, validate the manufacturing process, and produce a GMP clinical grade dAd5GNE vaccine. Aim 2. Execute IND-enabling preclinical efficacy and safety testing of the dAd5GNE product. Aim 3. Prepare and submit an IND package and gain approval from the FDA and other regulatory groups to initiate a phase I clinical trial. Aim 4. Carry out a phase I trial to assess the safety nd preliminary measure of efficacy of the dAd5GNE vaccine in humans. PUBLIC HEALTH RELEVANCE: Cocaine addiction is a major health problem for which there is no effective therapy. We have devel- oped an anti-cocaine vaccine dAd5GNE, a highly immunogenic disrupted serotype 5 human adenovi- rus to which a cocaine analog is coupled. Based on studies in mice, rats and nonhuman primates demonstrating dAd5GNE is highly effective in evoking anti-cocaine antibodies and suppressing the ability of cocaine to reach the brain, we propose to carry out the preclinical studies obtain regulatory approval and carry out a phase I safety and initial efficacy trial of dAd5GNE in cocaine addicts.